Our published preliminary studies indicate that pulmonary hypertension occurs in nearly one-third of adults with sickle cell disease, that it is associated with increased mortality although pulmonary artery pressures are lower than in patients with primary pulmonary hypertension, and that chronic hemolysis with nitric oxide scavenging may be a part of the pathogenesis. The present proposal is based on three postulates. First, the problem of sickle cell-associated pulmonary hypertension may begin during childhood and adolescence. A retrospective analysis and our own preliminary data suggest pulmonary hypertension prevalence of up to 25% in adolescents. Second, the pathogenesis of sickle cell-associated pulmonary hypertension may not only include the effects of chronic hemolysis, but also the consequences of chronic hypoxia related to severe anemia and repeated vasoocclusive episodes. Pulmonary hypertension is a recognized complication of conditions marked by chronic hypoxia, and we have recently found evidence that pulmonary hypertension complicates Chuvash polycythemia, a congenital disorder of oxygen sensing in which the hypoxic response is constitutively up regulated in the absence of hypoxia and in which high hemoglobin concentrations would promote nitric oxide scavenging. Third, the pathophysiology of sickle cell-associated pulmonary hypertension may be elucidated by comparing components of the hypoxic response in patients with sickle cell disease and Chuvash polycythemia according to the presence or absence of pulmonary hypertenson. Both sickle cell disease and Chuvash polycythemia may be characterized by nitric oxide scavenging and upregulated hypoxia inducible factor, leading to stimulation of pulmonary vascular proliferative pathways that eventuate in pulmonary hypertension. Comparing specific responses in both conditions may identify shared pathways that have a central role in sickle cell-related pulmonary hypertenison. This is an observational study of pulmonary hypertension in a) children and adolescents with sickle cell disease and b) children, adolescents and adults with sickle cell disease or Chuvash polycythemia. In both a and b there are two arms- one that contains patients and one that contains controls from the background population. As of May, 2007 221 children were enrolled, of whom 193 had SCD and 28 were controls. The mean (SD) age was 12 (5) years for both SCD patients and controls. The M:F ratio was 1.1 for patients and 0.9 for the controls. Eighty-two percent of the patients had hemoglobin SS or Sbeta0 thalessemia. TRV was measurable in 180 SCD patients and 26 controls. Median (and 5 to 95 percentile) TRVs were 2.3 (1.8 to 2.7) m/s in SCD patients and 2.1 (1.8 to 2.5) m/s in controls (P = 0.005). Thirty-five (19.4%) of the SCD patients had a TRV of 2.5 m/s or higher compared to 1 (3.8%) of the controls (P = 0.050). One patient (0.6%) and none of the controls had a TRV of 3.0 m/s or greater. In univariate analyses of clinical variables among the patients with SCD, TRV did not correlate significantly with age, systemic blood pressure, or histories of stroke, asthma or use of hydroxyurea, but it did correlate with histories of acute chest syndrome and pneumonia, SS or Sbeta0 thalassemia phenotype, degree of anemia, and markers of hemolysis (LDH, reticulocyte count, bilirubin). In multivariate logistic regression analysis, only history of acute chest syndrome (P = 0.015) and bilirubin concentration (P = 0.029) had independent associations with a TRV of ? 2.5 m/sec. History of acute chest syndrome was associated with 3.1-fold increase in the risk of TRV 2.5 m/s or higher (95% confidence interval (CI): 1.3-7.9) and each 2 mg/dL increase in bilirubin with a 1.6 fold higher risk (95% CI: 1.04-2.3). In univariate analyses of ECHO measurements, TRV did not correlate significantly with left ventricular (LV) ejection fraction or E/A ratio, but it did correlate significantly with E-ETDI, LV mass index and LV internal diastolic diameter Z-score. In multivariate logistic regression analysis, only LV mass index had a significant independent association with TRV of 2.5 m/s or higher (P = 0.005). Each 10 point increase in the LV mass index was associated with a 1.3-fold increase in the risk of TRV 2.5 m/s or higher (95% CI: 1.1-1.5). At this point of interim analysis, TRV is significantly higher in children and adolescents with SCD at steady state than age-matched control participants. Among clinical variables, higher TR velocities are linked independently to history of acute chest syndrome and degree of hemolysis as reflected in bilirubin concentration. Of echocardiogram variables, TRV of 2.5 m/s or higher has an independent association with higher LV mass index. Thus, in children with SCD, vaso-occlusive and hemolytic anemia complications as well as factors leading to LV enlargement, hypertrophy, and diastolic dysfunction may contribute to the development of pulmonary hypertension. The NIH Clinical Center does not enroll subjects under this protocol, but provides laboratory support and data management.